EP0083673A1 - Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts - Google Patents
Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts Download PDFInfo
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- EP0083673A1 EP0083673A1 EP82100130A EP82100130A EP0083673A1 EP 0083673 A1 EP0083673 A1 EP 0083673A1 EP 82100130 A EP82100130 A EP 82100130A EP 82100130 A EP82100130 A EP 82100130A EP 0083673 A1 EP0083673 A1 EP 0083673A1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/001—Preparations to induce tolerance to non-self, e.g. prior to transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00118—Cancer antigens from embryonic or fetal origin
Definitions
- immunological tolerance does not mean a reduction in the pharmacological effectiveness of the preparations used, but rather is It is possible that immunological reactions to the drug are also involved in the development of drug tolerance in the pharmacological sense.These are caused by the generation of an immunological tolerance, ie the suppression of antibody formation prevented against the drug.
- the corpuscular cell components that are used act as an adjuvant of the dissolved factors and prevent the creation of a tolerance against the preparation.
- immunological adjuvants are used to enhance the formation of antibodies, in order to generate an organ-specific stimulus from the resulting antibodies, especially in degenerative diseases and geriatric indications. This antibody formation is avoided when the fully soluble and emulsifiable organ dry powder is used according to the invention. Therefore the indications also differ.
- the state of the induced immunological tolerance remains as long as the antigen is present in the organism in sufficient concentration.
- the antigen must be continuously injected in mg to g concentrations in order to produce a stable immunological tolerance and to maintain it.
- the organ factors against which tolerance is desired need therefore be administered continuously, while there is no need to use other factors against which tolerance is no longer required. If the tolerogenic application is suspended for more than 5 days, a tolerance decrease is to be expected. Repeated treatment therefore makes it necessary to build up the tolerance again by means of creeping doses.
- they can be used as antigen for antigen-antibody reactions in vivo or in vitro to be used.
- the concentration is increased to pg, ng, H g to mg and possibly g / ml organ solution after a sensitivity test by conjunctival application or IC injection before the iv application. If the test result is positive, desensitization should be carried out with ic, sc or oral application according to allergy criteria. If the concentration ug is tolerated without reaction, the increasing concentrations can then be applied, starting from pg, iv.
- Cell therapy according to NIEHANS differs from the present application by the use of cell suspensions, while here fully soluble and emulsifiable organ preparations are used. Cell preparations cannot i.v. be applied.
- the fully water-soluble dry organ powder contains crystallized proteins, proteins, nucleic acids (ribonucleic acids and deoxyribonucleic acids), "peptides, enzymes, polysaccharides and lipids, as well as their subunits and constituents. It has been shown that mixtures of native macromolecules with their subunits produce tolerance to Chemical changes such as gentle hydrolysis and sulfation, phosphorylation, halogenation, nitration, carboxylation, ethylation, alkyl substitution, aromatic substitution, alkylation, arylation, also have a beneficial effect and improve the effectiveness compared to native aqueous fresh homogenates or lyophylizates up to 60%.
- the hydrogen ion concentration and the temperature during the workup are also decisive for the effectiveness of the end product (cf. EPA 801066.6).
- isolated partial factors from an organ type can also be used Organ combinations can be used. It is also possible to adjust the molecular weight by filtration and to standardize the preparations, for example according to the protein content or other active factors. Optimal effects were achieved with fully water-soluble organ dry powders, which were obtained by lyophilization of adjusted solutions, which are obtained by high-speed centrifugation and filtration from suspensions of sulfated dry powder (EPA 801066.6). In analog However, suspensions of lyophilized dry powders as well as fresh homogenates from organ tissues can also be worked up.
- the ratio of proteins or proteids to polysaccharides, nucleic acids and lipids among one another can be determined.
- emulsifiers or detergents eg sodium dodecyl sulfate in higher dilutions, which do not denature, lipids become emulsifiable. Partial extraction of whole organ extracts by lipid solvents and enzymatic degradation of undesirable factors are also possible.
- the fully soluble and emulsifiable organ dry powder can also be used together with solution-delaying carriers, pressed as tablets, dragees, granules or in capsules or microcapsules.
- Solutions of the organ dry powder can be applied incorporated in membranes made of polysaccharides, lipids or plastics.
- the solution-retarding carriers or binders, as well as the auxiliaries used as membrane substances can themselves be immunogenic and must then also be used immunologically tolerogenously, so that no antibody formation occurs. However, they must be metabolizable.
- a constant release of the active substances per unit of time is important, e.g. ng to mg / day from a certain amount by weight of the sustained-release preparation. The effectiveness of these preparations also depends on the full solubility of the active factors, so that special information is not necessary.
- the claimed indications are immunopathogenic auto-sensitization and auto-aggression caused by illness or by pre-treatment with cell therapy. There is desensitization and tolerance generation with analog organ types against which there is an antibody formation.
- the repeated systemic application of larger quantities of organs in the mg range and the use in sustained release form with a temporary release of the active substances leads to an improvement in the therapeutic effect and healing compared to the previously only one application of the higher concentrations.
- the previous immune barrier can be broken through prior generation and continuous maintenance of a stable upper cross tolerance against allogeneic and individual organ antigens.
- Retard and depot preparations can also be used to maintain the induced tolerance. Maintaining the tolerance induced against xenogenic or allogeneic organ factors makes organ transplantation independent of time. However, intensive pretreatment in the form of rapid tolerance generation through very short application intervals must be carried out at least 5 days before organ transplantation the increase to full dosage can be done. If there is a long distance before the organ transplant, the tolerance must be increased and maintained by increasing the dosage. Also after organ transplantation. The organ tolerance achieved can be checked by using the applied organ preparations or the donor's blood or tissue cells as an antigen before and after the organ transplant by antigen-antibody reaction.
- the heart muscle and parenchymatous organs as well as apoplexies also offer completely new possibilities through the preventive generation of tolerance as early as possible in the period up to the necrotic disintegration of the infarcted tissue.
- the cell contents that lead to auto-sensitization are only released after a few days.
- the resulting autoantibodies are held responsible for complications of the healing process and for the occurrence of reinfections.
- Induction of cross tolerance as early as possible prevents the development of autoantibodies and thus these complications.
- the tolerogenic treatment must therefore begin immediately after the infarction event and be carried out until it heals. There is nothing to prevent combination treatment with other intensive therapeutic methods.
- a cross-tolerance can be generated at least 5 days before the operation, similar to organ transplantation with preparations similar to those that are damaged during the surgical procedure.
- Malignant tumors e.g. breast cancer with bone metastases
- Malignant tumors are treated with single preparations from the maternal part of the placenta, youthful thymus, liver, spleen, pancreas, brain parts, umbilical cord or epiphysis together with the organ of the primary tumor or the location of the metastases, in this case Breast gland and bone marrow, together with juvenile test without spermatogenesis due to the hormone dependence of the tumor or with mixtures of at least 2 of the above-mentioned components in equal parts with immunologically tolerant dosing of the aqueous solutions in dilutions pg, ng, ⁇ g and mg from the fully water-soluble and emulsifiable Organ dry substances or powders.
- the treatment can be carried out as an interval treatment until the symptoms disappear or as a 3-week course. A repetition is possible at any time if the condition worsens again, but otherwise at increasing intervals of 2, 3, 4 and 6 months. For tumor prevention in high-risk patients, repeat cures are carried out at intervals of 1/2 to 1 year.
- prostate preparations that correspond to the topsoil of the metastases and those from the ovary are used. A similar procedure is used for other types of tumors.
- immunological tolerance is first induced by systemic use, also against preparations from brain parts, and then from the 3rd week of treatment, in addition to the tolerance-preserving application, 2-4 ml of the concentrations pg, ng ug in intervals of 3-4 days , possibly also mg applied. Otherwise, other tumor types can be injected intra-tumoral, -pleural, -peritoneal, -articular after the immune tolerance to the preparation has been established.
- Those obtained by the method of EPA 801066.6 can also be used immunogenically from the standpoint of immunological immunization by booster. To maintain tolerance to the directly effective factors, these must be administered continuously as described. It can also be used as a depot or sustained release preparation.
- the treatment regimen differs from example 1 in that only 2-4 ml of the different dilution levels are used. The treatment is continued for 1-2 weeks after the symptoms have disappeared.
- the application can also be s.c. or i.m. respectively.
- the IV application is used as an injection or as an infusion, starting with the highest initial dilution of 2-4 ml of the increasing concentration up to mg / ml.
- Simultaneously combined use of preparations according to Example 2 accelerates the success of the therapy. This could be objectified by a decrease in the existing eosinophilia of lymphocytosis and the autoantibody.
- Example 2 To produce upper cross tolerance before an allogeneic kidney transplantation, at least 5 days before the transplantation, but if possible 2-3 weeks beforehand, treatment with preparations from fetal and juvenile pig kidney is carried out in a similar manner as in Example 1. Mixed preparations according to Example 2 can also be used. In order to maintain a stable tolerance, every 3-4 days up to g quantities in concentrations mg / ml initially i.v. Applied and later implanted sustained release preparations that release protein amounts of ⁇ g to mg per day.
- preparations analogous to the organ type concerned are applied as early as possible after the infarction event with a rapid increase in concentration as in Example 1.
- mixed preparations according to Example 2 can be used.
- Treatment continues until clinical healing and normalization of laboratory parameters.
- intrathecal administration of 1-2 ml of the dilutions pg and ng is also carried out from the 3rd day.
- the treatment can be carried out in addition to the usual intensive therapy.
- the concentrations and application quantities may only be increased if they are perfectly tolerable, otherwise the concentration and the application quantity must be increased by at least 1-2 steps, i.e. Decimal can be lowered. This applies to all indications.
- soluble organ preparations as an antigen for testing for existing antibody formation.
- the preventive or therapeutically used solutions of ⁇ g and mg / ml against blood serum or body fluids such as liquor spinalis, joint punctates, exudates in the gel are Diffusion test examined.
- the preparations can also be used radioactively labeled for radioimmunoassay (RIA test).
- RIA test radioimmunoassay
- allergen tests are possible in vivo, eg conjunctival, epidermal and intracutaneous.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Gynecology & Obstetrics (AREA)
- Oncology (AREA)
- Developmental Biology & Embryology (AREA)
- Reproductive Health (AREA)
- Pregnancy & Childbirth (AREA)
- Transplantation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Bei der tierexperimentellen und therapeutischen Anwendung in der Humanmedizin von xenogenen, d.h. von artverschiedenen Individuen stammenden Totalextrakten aus verschiedenen Organarten, insbesondere dem maternen Anteil der Rinderplazenta (Decidua), jugendlicher und foetaler Leber, Milz, Thymus, Knochenmark, Gehirnanteilen, einzeln und in Mischungen, wurde festgestellt, daß die therapeutische Wirkung dosis- und zeitabhängig ist. Insbesondere zeigte sich dies bei der Regression von Malignomen und Tumormetastasen. Es sind dazu wiederholte Behandlungen in mg- bis g-Dosen erforderlich. Diese Dosierung führt zur immunologischen Sensibilisierung, zu allergischen Reaktionen und zu einer Wirkungseinschränkung, insbesondere bei späteren Wiederholungsbehandlungen. Andererseits hat die Anwendung an Zellkulturen gezeigt, daß die Wirkung dort auch bei Wiederholungsbehandlungen reproduzierbar war und daß diese Wirkung durch Inhibition der Organextrakte mit den entsprechenden Antikörpern verhindert wird. Es war deshalb anzunehmen, daß auch in vivo die Blockierung der tumorhemmenden Wirkung der Organpräparate auf einer Antikörperbildung gegen dieselben beruht. Während allergisch-anaphylaktische Reaktionen heute durch symptomatische Therapie zu beherrschen sind, eignen sich die üblichen immunsuppressiven Maßnahmen, wie z.B. die Anwendung von Zytostatika, Kortikoiden oder ionisierenden Strahlen nicht zur Unterdrückung der Antikörperbildung gegen die allogenen oder xenogenen Organextrakte, weil dadurch auch die erwünschte Antikörperbildung gegen Tumorzellen und Infektionserreger unterdrückt werden würde. Die Erzeugung einer spezifischen Immuntoleranz gegen die therapeutisch wirksamen Organfaktoren war bei den relativ hohen erforderlichen Konzentrationen in bisher bekannter Weise nicht möglich. Es wurde nun aber gefunden, daß durch intravasale Applikation von wasserlöslichen und emulgierbaren Organtrockenpulvern in ansteigender Dosierung und sich verlängernden Zeitabständen eine ausreichend stabile Toleranz für die wiederholten Anwendungen der therapeutisch erforderlichen, höheren Konzentrationen erreicht wurde, wenn die Endkonzentration im mg- bis g-Bereich/ml Lösungsmittel liegt. Solche Lösungen sind jedoch nicht haltbar und fallen rasch aus, so daß sie unmittelbar vor der Anwendung aus vollöslichen bzw. emulgierbaren Organtrockenpulvern hergestellt werden müssen. Die Steigerung der Konzentrationen erfolgt mindestens über 2 Verdünnungsstufen, normalerweise über pg, ng, ug, in sich verlängernden Intervallen von Stunden bis zu 3-5 Tagen. Auf diese Weise können alle Arten von voll wasserlöslichen und emulgierbaren antigenen Organtrockenpulvern angewandt werden. Nach Erzeugung der immunologischen Toleranz sind alle bekannten Applikationsformen, auch bei lokaler Anwendung, möglich. Die Toleranz sollte aber durch weitere systemische Anwendung unterhalten werden.In animal experimental and therapeutic use in human medicine from xenogeneic, ie total extracts from different organ species, especially from the material part of the bovine placenta (decidua), juvenile and fetal liver, spleen, thymus, bone marrow, brain parts, individually and in mixtures, it was found that the therapeutic effect is dose and time dependent. This was particularly evident in the regression of malignancies and tumor metastases. Repeated treatments in mg to g doses are required. This dosage leads to immunological sensitization, to allergic reactions and to an effect restriction, especially in later repeat treatments. On the other hand, the use on cell cultures has shown that the effect there was reproducible even with repeated treatments and that this effect is prevented by inhibiting the organ extracts with the corresponding antibodies. It was therefore to be assumed that the blocking of the tumor-inhibiting effect of the organ preparations on the formation of antibodies against in vivo the same is based. While allergic-anaphylactic reactions can today be controlled by symptomatic therapy, the usual immunosuppressive measures, such as the use of cytostatics, corticoids or ionizing radiation, are not suitable for suppressing the formation of antibodies against the allogeneic or xenogeneic organ extracts, because this also causes the desired antibody formation against Tumor cells and infectious agents would be suppressed. The generation of a specific immune tolerance against the therapeutically effective organ factors was not possible in the previously known manner at the relatively high concentrations required. It has now been found, however, that intravascular application of water-soluble and emulsifiable organ dry powders in increasing doses and with increasing time intervals has achieved a sufficiently stable tolerance for the repeated use of the therapeutically required higher concentrations if the final concentration in the mg to g range / ml of solvent. However, such solutions are not stable and precipitate quickly, so that they have to be prepared from fully soluble or emulsifiable organic dry powders immediately before use. The concentrations are increased at least over 2 dilution levels, usually over pg, ng, ug, in increasing intervals of hours up to 3-5 days. In this way, all types of fully water-soluble and emulsifiable antigenic organ powder can be used. After generating the immunological tolerance, all known forms of application are possible, even with local application. However, the tolerance should be maintained through further systemic application.
Die immunologische Toleranz bedeutet im Gegensatz zum Begriff der Arzneimittel-Toleranz (vgl. A. SCHREY: Toleranz bei Nitratpräparaten: Med. Klinik A.25.S.24 /699 (1981) nicht eine Verringerung der pharmakologischen Wirksamkeit der angewanten Präparate, vielmehr wird gerade diese durch die immunologische Toleranz gegen das Arzneimittel erhalten. Es erscheint möglich, daß an der Entstehung von Arzneimittel-Toleranz im pharmakologischen Sinne ebenfalls immunologische Re- aktionen gegen das Arzneimittel beteiligt sind. Diese werden durch Erzeugung einer immunologischen Toleranz, d.h. die Unterdrückung der Antikörperbildung gegen das Arzneimittel verhindert.In contrast to the concept of drug tolerance (cf. A. SCHREY: Tolerance in nitrate preparations: Med. Klinik A.25.S.24 / 699 (1981), immunological tolerance does not mean a reduction in the pharmacological effectiveness of the preparations used, but rather is It is possible that immunological reactions to the drug are also involved in the development of drug tolerance in the pharmacological sense.These are caused by the generation of an immunological tolerance, ie the suppression of antibody formation prevented against the drug.
Die Toleranzerzeugung gegen xenogene Antikörperseren, wie sie aus der Serum-Therapie von Infektionskrankheiten bekannt ist, betrifft vollkommen andere Indikationen und keine Inhaltsstoffe von Zellgeweben. Im Prinzip sollen dadurch allergisch-anaphylaktische Reaktionen verhindert werden. Sie dient also nicht der Erhaltung der therapeutischen Wirksamkeit der angewandten Antikörperseren (vgl. W. GRONEMEYER, H. SCHMIDT in K. HANSEN: Lehrbuch der Allergie, Georg Thieme Verlag Stuttgart, 1957).The tolerance generation against xenogeneic antibody sera, as is known from the serum therapy of infectious diseases, concerns completely different indications and no components of cell tissues. In principle, this is intended to prevent allergic-anaphylactic reactions. It is therefore not used to maintain the therapeutic effectiveness of the antibody sera used (cf. W. GRONEMEYER, H. SCHMIDT in K. HANSEN: Textbook of Allergy, Georg Thieme Verlag Stuttgart, 1957).
Auch die Desensibilisierung mit sogenannten Organ-Dilutionen im Rahmen der Zytoplasmatischen Therapie (vgl. Leitfaden der Zytoplasmatischen Therapie: vitOrgan Arzneimittel GmbH, 7302 Ostfildern 1 b. Stuttgart) besitzt unterschiedliche Indikationen und Anwendungsformen. Es handelt sich dabei um keine echten Lösungen und Emulsionen der Organsubstanzen, vielmehr enthalten diese noch korpuskuläre Bestandteile. Deshalb können die Konzentrationen im ng-- und ug-Bereich nicht i.v.Desensitization with so-called organ dilutions as part of cytoplasmic therapy (cf. guidelines for cytoplasmic therapy: vitOrgan Arzneimittel GmbH, 7302 Ostfildern 1 b. Stuttgart) also has different indications and forms of use. These are not real solutions and emulsions of the organ substances, rather they still contain corpuscular components. Therefore, the concentrations in the ng and ug range cannot i.v.
angewandt werden. Desgleichen auch nicht die Suspensionen aus den Trockensubstanzen. Suspensionen von diesen können nur intramuskulär appliziert werden. Die mitverwendeten korpuskulären Zellbestandteile wirken als Adjuvans der gelösten Faktoren immunogen und verhindern eine Toleranzerzeugung gegen das Präparat. Auch werden zusätzlich immunologische Adjuvantien zur Verstärkung der Antikörperbildung mitverwendet,um besonders bei degenerativen Erkrankungen und geriatrischen Indikationen einen organspezifischen Reiz durch die entstehenden Antikörper zu erzeugen. Bei der erfindungsaemäβen Anwendung der volllöslichen und emulgierbaren Organtrockenpulver wird jedoch diese Antikörperbildung vermieden. Deshalb unterscheiden sich auch die Indikationen. Der Zustand der induzierten immunologischen Toleranz bleibt solange erhalten, als das Antigen in ausreichender Konzentration im Organismus vorhanden ist. Deshalb muß zur Erzeugung einer stabilen immunologischen Toleranz und deren Aufrechterhaltung das Antigen in mg- bis g-Konzentrationen fortlaufend injiziert werden. Bei Kombinationsbehandlungen mit Antigenmischungen aus verschiedenen Organen müssen deshalb die Organfaktoren gegen die die Toleranz erwünscht ist, fortlaufend verabfolgt werden, während man andere Faktoren gegen die eine Toleranz nicht mehr benötigt wird, nicht weiter anzuwenden braucht. Nach Aussetzen der tolerogenen Applikation von mehr als 5 Tagen ist mit einem Toleranzverfall zu rechnen. Eine Wiederholungsbehandlung macht es deshalb notwendig, erneut die Toleranz durch einschleichende Dosierungen wieder aufzubauen. Zur Prüfung der Toleranz bzw. einer möglichen Sensibilisierung gegen die verwendeten Präparate können diese als Antigen für Antigen-Antikörper-Reaktionen in vivo oder in vitro benutzt werden. Bei vorliegender Sensibilisierung muß die Behandlung mit umso höheren Verdünnungen wieder begonnen werden, je ausgeprägter die Sensibilisierung ist. Umso kürzer müssen dann auch die Applikationsabstände gewählt werden. Normalerweise wird die Konzentration über pg, ng, Hg auf mg und eventuell g/ml Organlösung gesteigert, nachdem man vor der i.v.-Applikation einen Sensibilitätstest durch konjunktivale Anwendung oder i.c.-·Injektion durchführt. Bei positivem Testergebnis sollte eine Desensibilisierung bei i.c.-, s.c.- oder oraler Applikation nach den Gesichtspunkten der Allergologie durchgeführt werden. Bei reaktionsfreier Verträglichkeit der Konzentration ug kann dann die Applikation der ansteigenden Konzentrationen, beginnend von pg, i.v. erfolgen. Es ist möglich Faktoren gegen die eine Antikörperbildung unterbunden werden soll zunächst tolerogen zu dosieren und nach eingetretener Toleranz dann andersartige Faktoren, die indirekt über Antikörper zur Wirkung gelangen, wie z.B. Faktoren die durch das Verfahren zur Isolierung von wirksamen Faktoren aus biologischen Geweben (EPA 801066.6) gewonnen wurden, immunogen zu dosieren. Dabei bleibt dann die vorher induzierte Toleranz gegen die zuerst angewandten andersartigen Faktoren erhalten, sodaß sich die Antikörperbildung ausschließlich gegen die immunogen dosierten Faktoren richtet.be applied. Likewise, not the suspensions from the dry substances. Suspensions of these can only be applied intramuscularly. The corpuscular cell components that are used act as an adjuvant of the dissolved factors and prevent the creation of a tolerance against the preparation. In addition, immunological adjuvants are used to enhance the formation of antibodies, in order to generate an organ-specific stimulus from the resulting antibodies, especially in degenerative diseases and geriatric indications. This antibody formation is avoided when the fully soluble and emulsifiable organ dry powder is used according to the invention. Therefore the indications also differ. The state of the induced immunological tolerance remains as long as the antigen is present in the organism in sufficient concentration. Therefore, the antigen must be continuously injected in mg to g concentrations in order to produce a stable immunological tolerance and to maintain it. In combination treatments with antigen mixtures from different organs, the organ factors against which tolerance is desired need therefore be administered continuously, while there is no need to use other factors against which tolerance is no longer required. If the tolerogenic application is suspended for more than 5 days, a tolerance decrease is to be expected. Repeated treatment therefore makes it necessary to build up the tolerance again by means of creeping doses. To test the tolerance or a possible sensitization to the preparations used, they can be used as antigen for antigen-antibody reactions in vivo or in vitro to be used. If the sensitization is present, the treatment with higher dilutions must be started again, the more pronounced the sensitization is. The shorter the application intervals must be. Normally the concentration is increased to pg, ng, H g to mg and possibly g / ml organ solution after a sensitivity test by conjunctival application or IC injection before the iv application. If the test result is positive, desensitization should be carried out with ic, sc or oral application according to allergy criteria. If the concentration ug is tolerated without reaction, the increasing concentrations can then be applied, starting from pg, iv. It is possible to dose factors against which the formation of antibodies should first be tolerogenously and then after tolerance has occurred, other types of factors which have an indirect effect via antibodies, such as factors caused by the process for isolating effective factors from biological tissues (EPA 801066.6) were obtained to dose immunogen. The previously induced tolerance against the other applied factors is then maintained, so that the antibody formation is directed exclusively against the immunogenically dosed factors.
Die Zelltherapie nach NIEHANS unterscheidet sich von vorliegender Anwendung durch die Verwendung von Zellsuspensionen, während hier voll lösliche und emulgierbare Organpräparate verwendet werden. Zellpräparate können nicht i.v. appliziert werden.Cell therapy according to NIEHANS differs from the present application by the use of cell suspensions, while here fully soluble and emulsifiable organ preparations are used. Cell preparations cannot i.v. be applied.
Die wiederholte Injektionsimplantation größerer Mengen kann zur pathogenen Allergisierung oder aber zur Immunparalyse führen. Letztere bedeutet eine Blockierung des Immunsystems, sodaß auch erwünschte Antikörper ausbleiben. Wiederholungsbehandlungen sind erst nach Monaten möglich, wenn sich die Sensibilisierung spontan verloren hat.Repeated injection implantation of larger quantities can lead to pathogenic allergy or to immune paralysis. The latter means that the immune system is blocked, so that there are no desired antibodies. Repeat treatments are only possible after months if the sensitization has spontaneously disappeared.
Die voll wasserlöslichen Organtrockenpulver enthalten kristallisierte Proteide, Proteine, Nukleinsäuren (Ribonukleinsäuren und Desoxyribonukleinsäuren), " Peptide, Enzyme, Polysaccharide und Lipide, sowie deren Untereinheiten und Bestandteile. Es hat sich gezeigt, daß Mischungen von nativen Makromolekülen mit ihren Untereinheiten die Erzeugung von Toleranz gegen die angewandten Präparate erleichert. Ebenso wirken sich chemische Veränderungen wie z.B. schonende Hydrolyse und Sulfatierung, Phosphorylierung, Halogenisierung, Nitrierung, Carboxylierung, Äthylierung, Alkylsubstitution, aromatische Substitution, Alkylierung, Arylierung, günstig aus und verbessern die Wirksamkeit gegenüber nativen wässrigen Frischhomogenaten oder -lyophylisaten um bis zu 60%. Die Wasserstoffionenkonzentration und die Temperatur während der Aufarbeitung sind für die Wirksamkeit des Endproduktes ebenfalls entscheidend (vgl. EPA 801066.6). Wie erwähnt können auch isolierte Teilfaktoren aus einer Organart, wie auch Organkombinationen angewandt werden. Es ist auch möglich, das Molekulargewicht durch Filtration einzustellen und die Präparate z.B. nach dem Eiweißgehalt oder anderen Wirkfaktoren zu standardisieren. Optimale Wirkungen wurden mit voll wasserlöslichen Organtrockenpulvern erzielt, die durch Lyophilisation eingestellter Lösungen erhalten wurden, die durch hochtourige Zentrifugation und Filtration aus Suspensionen von sulfatierten Trokkenpulvern (EPA 801066.6) gewonnen werden. In analoger Weise können aber auch Suspensionen von lyophilisierten Trockenpulvern wie auch Frischhomogenate aus Organgeweben aufgearbeitet werden. Das Verhältnis von Proteinen bzw. Proteiden zu Polysacchariden, Nukleinsäuren und Lipiden untereinander kann festgelegt werden. Durch Mitverwendung von Emulgatoren bzw. Detergentien, z.B. Natriumdodecylsulfat in höheren Verdünnungen, die nicht denaturieren, werden Lipide emulgierbar. Auch ist eine partielle Extraktion der Organvollextrakte durch Lipidlösungsmittel wie auch ein enzymatischer Abbau unerwünschter Faktoren möglich.The fully water-soluble dry organ powder contains crystallized proteins, proteins, nucleic acids (ribonucleic acids and deoxyribonucleic acids), "peptides, enzymes, polysaccharides and lipids, as well as their subunits and constituents. It has been shown that mixtures of native macromolecules with their subunits produce tolerance to Chemical changes such as gentle hydrolysis and sulfation, phosphorylation, halogenation, nitration, carboxylation, ethylation, alkyl substitution, aromatic substitution, alkylation, arylation, also have a beneficial effect and improve the effectiveness compared to native aqueous fresh homogenates or lyophylizates up to 60%. The hydrogen ion concentration and the temperature during the workup are also decisive for the effectiveness of the end product (cf. EPA 801066.6). As mentioned, isolated partial factors from an organ type can also be used Organ combinations can be used. It is also possible to adjust the molecular weight by filtration and to standardize the preparations, for example according to the protein content or other active factors. Optimal effects were achieved with fully water-soluble organ dry powders, which were obtained by lyophilization of adjusted solutions, which are obtained by high-speed centrifugation and filtration from suspensions of sulfated dry powder (EPA 801066.6). In analog However, suspensions of lyophilized dry powders as well as fresh homogenates from organ tissues can also be worked up. The ratio of proteins or proteids to polysaccharides, nucleic acids and lipids among one another can be determined. By using emulsifiers or detergents, eg sodium dodecyl sulfate in higher dilutions, which do not denature, lipids become emulsifiable. Partial extraction of whole organ extracts by lipid solvents and enzymatic degradation of undesirable factors are also possible.
Die voll löslichen und emulgierbaren Organtrockenpulver können auch zusammen mit lösungsverzögernden Trägerstoffen, gepresst als Tabletten, Dragees,'Granulat oder auch in Kapseln bzw. Mikrokapseln angewandt werden. Lösungen der Organtrockenpulver können inkorporiert in Membranen aus Polysacchariden, Lipiden oder Kunststoffen appliziert werden. Die lösungsverzögernden Träger- oder Bindestoffe, ebenso die als Membranstoffe verwendeten Hilfsstoffe können selbst immunogen sein und müssen dann ebenfalls immunologisch tolerogen angewandt werden, sodaß eine Antikörperbildung unterbleibt. Sie müssen jedoch metabolisierbar sein. Für die Depot- oder Retard-Wirkung ist eine konstante Freisetzung der Wirkstoffe pro Zeiteinheit wichtig, z.B. ng bis mg/Tag aus einer bestimmten Gewichtsmenge des Retard-Präparates. Die Wirkung auch dieser Präparate ist von der vollen Löslichkeit der Wirkfaktoren abhängig, sodaß sich spezielle Angaben erübrigen.The fully soluble and emulsifiable organ dry powder can also be used together with solution-delaying carriers, pressed as tablets, dragees, granules or in capsules or microcapsules. Solutions of the organ dry powder can be applied incorporated in membranes made of polysaccharides, lipids or plastics. The solution-retarding carriers or binders, as well as the auxiliaries used as membrane substances, can themselves be immunogenic and must then also be used immunologically tolerogenously, so that no antibody formation occurs. However, they must be metabolizable. For the depot or sustained release effect, a constant release of the active substances per unit of time is important, e.g. ng to mg / day from a certain amount by weight of the sustained-release preparation. The effectiveness of these preparations also depends on the full solubility of the active factors, so that special information is not necessary.
Zur systemischen Applikation hat sich auch die Inhalation von Aerosolen bewährt. Zur Vernebelung können Lösungen, wie auch Suspensionen mit Liposomen, in denen d4e Lösungen eingeschlossen sind, verwendet werden.Inhalation of aerosols has also proven itself for systemic application. For nebulization, solutions as well as suspensions with liposomes, in which the d4e solutions are included, can be used.
Prinzipiell sind alle Applikationsformen zur Anwendung geeignet, auch über Haut und Schleimhäute, sowie oral, wie auch in Form von Wasser-in-öl-Emulsionen in dünndarmlöslichen Kapseln oder inkorporiert in Liposomen. Grundvoraussetzung ist die Induktion und Erhaltung von immunologischer Toleranz über eine sogenannte Low-Zone-Toleranz (vgl. J.H. HUMPHREY und R. WHITE: Kurzes Lehrbuch der Immunologie: Georg Thieme Verlag, Stuttgart), die jedoch bis zu höheren Konzentrationen im mg- bis g-Bereich erweitert wird. Die alleinige Low-Zone-Toleranz wird sonst aufgrund von Verdünnungen von pg bis ug durch die therapeutisch erforderlichen Konzentrationen der Organextrakte durchbrochen. Ebenso wichtig sind auch die sich verlängernden Applikationsabstände von Stunden bis höchstens 3-5 Tagen bei gleichzeitig ansteigender Dosierung und möglichst die i.v.-Injektion bzw.-Infusion. Die Anwendung von Depot- und Retard-Präparaten bietet dann für die Toleranzerhaltung Vorteile. Dieses Vorgehen besitzt gegenüber der Erzeugung von High-Zone-Toleranz den Vorteil, daß die erwünschten Reaktionen des Immunsystems gegen andere Antigene, z.B. Tumor- oder Infektions-spezifische Antigene nicht beeinträchtigt werden, also keine allgemeine Immunparalyse-eintritt. Trotzdem erfolgt durch ansteigende Dosierung auf Konzentrationen von mg bis g/ml Lösungsmittel eine Erweiterung der Toleranz auf phylogenetisch verwandte Antigene. Es entsteht dabei eine Art Oberkreuz-Toleranz bezüglich der xenogenen Antigene und allogener bzw. individueller Antigenqualitäten wie sie in den körpereigenen, entsprechenden Organarten vorkommen. Dies eröffnet weitere wichtige Indikationsgebiete dieser immunologisch tolerogenen Anwendung von voll wasserlöslichen bzw. emulgierbaren Organtrockenpulvern aus unterschiedlichen Organarten, einzeln und in Mischungen.In principle, all forms of application are suitable for use, also via the skin and mucous membranes, and orally, as well as in the form of water-in-oil emulsions in small intestine-soluble capsules or incorporated in liposomes. The basic requirement is the induction and maintenance of immunological tolerance via a so-called low-zone tolerance (cf.JH HUMPHREY and R. WHITE: Short textbook on immunology: Georg Thieme Verlag, Stuttgart), which, however, up to higher concentrations in the mg to g Area is expanded. The sole low-zone tolerance is otherwise broken due to dilutions from pg to µg by the therapeutically required concentrations of the organ extracts. Equally important are the lengthening application intervals of hours to a maximum of 3-5 days with increasing dosage and, if possible, IV injection or infusion. The use of depot and retard preparations then offers advantages for maintaining tolerance. This approach has the advantage over producing high zone tolerance that the desired immune system responses to other antigens, e.g. Tumor- or infection-specific antigens are not affected, i.e. no general immune paralysis occurs. Nevertheless, the tolerance increases to phylogenetically related antigens by increasing the dosage to concentrations from mg to g / ml of solvent. This creates a kind of upper cross tolerance with regard to the xenogenic antigens and allogeneic or individual antigen qualities as they occur in the body's corresponding organ types. This opens up further important areas of indication for this immunologically tolerogenic application of fully water-soluble or emulsifiable organ dry powder from different organ types, individually and in mixtures.
Die beanspruchten Indikationen sind krankheitsbedingte oder durch Vorbehandlung mit Zelltherapie entstandene immunopathogenen Autosensibilisierungen und Autoaggressionen. Es erfolgt dort eine Desensibilisierung und Toleranzerzeugung mit analogen Organarten gegen die eine Antikörperbildung besteht. Die wiederholte systemische Applikation größerer Organmengen im mg-Bereich und die Anwendung in Retard-Form mit zeitlich begrenzter Freisetzung der Wirksubstanzen führt gegenüber der bisher nur einmaligen Anwendung der höheren Konzentrationen zur Verbesserung der therapeutischen Wirkung und zur Ausheilung.The claimed indications are immunopathogenic auto-sensitization and auto-aggression caused by illness or by pre-treatment with cell therapy. There is desensitization and tolerance generation with analog organ types against which there is an antibody formation. The repeated systemic application of larger quantities of organs in the mg range and the use in sustained release form with a temporary release of the active substances leads to an improvement in the therapeutic effect and healing compared to the previously only one application of the higher concentrations.
Genetisch oder chromosomal bedingte Erkrankungen bedürfen einer ständigen Substitution von Faktoren aus Stoffwechsel-gesunden Zellen und Geweben in einer Dosierung die sonst die Gefahr einer Antikörperbildung gegen die wirksamen Faktoren einschließt. Bei der Zelltherapie nach NIEHANS sind deshalb Wiederholungsbehandlungen beim Down-Syndrom nur in Abständen von frühestens 1/2 Jahr bis 1 Jahr möglich. Die immunologisch tolerogene Anwendung erlaubt nun eine Dauerbehandlung, auch unter Verwendung von Depot- und Retard-Präparaten.Genetically or chromosomally related diseases require constant substitution of factors from metabolically healthy cells and tissues in a dosage that otherwise includes the risk of antibody formation against the active factors. With NIEHANS cell therapy, repeat treatments for Down syndrome are therefore only possible at intervals of 1/2 year to 1 year at the earliest. The immunologically tolerogenic application now allows long-term treatment, also using depot and retard preparations.
Bei Organtransplantaten kann durch vorherige Erzeugung und fortlaufende Unterhaltung einer stabilen Oberkreuz-Toleranz gegen allogene und individuelle Organ-Antigene die bisher bestehende Immunbarriere durchbrochen werden. Auch hier lassen sich zur Aufrechterhaltung der induzierten Toleranz Retard- und Depot-Präparate verwenden. Die Aufrechterhaltung der gegen xenogene oder allogene Organfaktoren induzierten Toleranz macht die Organtransplantation zeitlich unabhängig. Es muß aber mindestens 5 Tage vor der Organverpflanzung eine intensive Vorbehandlung in Form der Schnellerzeugung von Toleranz durch sehr kurze Applikatiosintervalle der Anstieg zur Volldosierung durchgeführt werden. Bei längerem Abstand bis zur Organtransplantation muß die Toleranz durch weiter ansteigende Dosierung verstärkt und aufrecht erhalten werden. Ebenso auch nach erfolgter Organtransplantation. Die erreichte Organtoleranz kann durch Verwendung der applizierten Organpräparate oder von Blut- bzw. Gewebezellen des Spenders als Antigen vor und nach der Organtransplantation durch Antigen-Antikörper-Reaktion überprüft werden.In the case of organ transplants, the previous immune barrier can be broken through prior generation and continuous maintenance of a stable upper cross tolerance against allogeneic and individual organ antigens. Retard and depot preparations can also be used to maintain the induced tolerance. Maintaining the tolerance induced against xenogenic or allogeneic organ factors makes organ transplantation independent of time. However, intensive pretreatment in the form of rapid tolerance generation through very short application intervals must be carried out at least 5 days before organ transplantation the increase to full dosage can be done. If there is a long distance before the organ transplant, the tolerance must be increased and maintained by increasing the dosage. Also after organ transplantation. The organ tolerance achieved can be checked by using the applied organ preparations or the donor's blood or tissue cells as an antigen before and after the organ transplant by antigen-antibody reaction.
Bei Organinfarkten, z.B. vom Herzmuskel und parenchymatösen Organen sowie Apoplexien bieten sich ebenfalls vollkommen neue Möglichkeiten durch die präventive, möglichst frühzeitige Toleranzerzeugung in der Zeit bis zum nekrotischen Zerfall des infarzierten Gewebes. Die Freisetzung der Zellinhaltsstoffe die zur Autosensibilisierung führt, erfolgt erst nach einigen Tagen. Die entstehenden Autoantikörper werden für Komplikationen des Heilungsverlaufs und für das Auftreten von Reinfarkten verantwortlich gemacht. Die möglichst frühzeitige Induktion von Überkreuz-Toleranz verhindert die Entstehung von Autoantikörpern und damit diese Komplikationen. Die tolerogene Behandlung muß deshalb gleich nach dem Infarktereignis einsetzen und bis zur Abheilung durchgeführt werden. Einer Kombinationsbehandlung mit anderen intensiv-therapeutischen Methoden steht nichts im Wege.For organ infarctions, e.g. The heart muscle and parenchymatous organs as well as apoplexies also offer completely new possibilities through the preventive generation of tolerance as early as possible in the period up to the necrotic disintegration of the infarcted tissue. The cell contents that lead to auto-sensitization are only released after a few days. The resulting autoantibodies are held responsible for complications of the healing process and for the occurrence of reinfections. Induction of cross tolerance as early as possible prevents the development of autoantibodies and thus these complications. The tolerogenic treatment must therefore begin immediately after the infarction event and be carried out until it heals. There is nothing to prevent combination treatment with other intensive therapeutic methods.
Zur Prävention von Operationsfolgen die ebenfalls auf der Basis einer Autosensibilisierung beruhen, kann ähnlich wie bei der Organtransplantation mit Präparaten analog denen, die bei dem chirurgischen Eingriff geschädigt werden, mindestens 5 Tage vor Operation eine Überkreuz-Toleranz erzeugt werden.To prevent the consequences of surgery, which is also based on auto-sensitization, a cross-tolerance can be generated at least 5 days before the operation, similar to organ transplantation with preparations similar to those that are damaged during the surgical procedure.
Bei Verbrennungen steht kein längeres Intervall bis zur Bildung von Autoantikörpern zur Verfügung. Trotzdem kann auch hier gleich eine entsprechende Behandlung mit Präparaten analog den verbrannten Geweben stattfinden. Bei Verbrennungen wie auch bei Operationsfolgen geht es aber auch darum, die Intensität der Sensibilisierungsvorgänge durch Organpräparate, insbesondere aus foetalem Thymus, foetaler Milz, foetalem Anteil der Plazenta, Nebenniere und Lymphknoten in Form von Einzel- oder Kombinationspräpraten zu verringern. Die tolerogene Dosierung ist hier auf die eingesetzten Präparate bezogen und nicht auf die eigentlich geschädigten Organe. Diese allgemeine biologische Immunsuppression kommt bei allen Erkrankungen in Betracht, die auf Autoantikörperbildung beruhen, insbesondere auch bei Erkrankungen der Gelenke und des Zentralnervensystems. Sie kann als Kombinationsbehandlung zusammen mit der gezielten Toleranzerzeugung gegen bestimmte Organe oder Organkombinationen durchgeführt werden.In the case of burns, there is no longer an interval until the formation of autoantibodies. Nevertheless, a corresponding treatment with preparations analogous to the burned tissues can also take place here. In the case of burns as well as the consequences of surgery, it is also a matter of reducing the intensity of the sensitization processes through organ preparations, in particular from fetal thymus, fetal spleen, fetal part of the placenta, adrenal gland and lymph nodes in the form of single or combination preparations. The tolerogenic dosage here is based on the preparations used and not on the organs that are actually damaged. This general biological immunosuppression can be used for all diseases that are based on autoantibody formation, in particular also for diseases of the joints and the central nervous system. It can be carried out as a combination treatment together with the targeted creation of tolerance against certain organs or organ combinations.
Es erscheint möglich, daß es im Gegensatz zu Adjuvantien, die die Immunogenität verstärken, auch solche gibt, die die Toleranzbildung verstärken können. Zu denken ist dabei an Nukleotide oder Nukleoside oder permeabilitätsverändernde Stoffe wie z.B. Dinatriumchromoglycat. Solche toleranzbegünstigende. Adjuvantien können bei den angegebenen Indikationen zusätzlich mitverwendet werden. Für die Behandlung für Krebskrankheiten erscheint jedoch eine allgemeine Immunsuppression oder die zusätzliche Anwendung solcher toleranzbegünstigender Medikamente nicht geeignet, weil dadurch die phylakogene Immunabwehr beeinträchtigt werden Die folgenden Beispiele erläutern die praktische Anwendung.It appears possible that, in contrast to adjuvants that increase immunogenicity, there are also those that can increase tolerance. One has to think of nucleotides or nucleosides or permeability-changing substances such as disodium chromoglycate. Such tolerance-promoting. Adjuvants can also be used for the indicated indications. However, general immunosuppression or the additional use of such tolerance-enhancing medications does not appear to be suitable for the treatment of cancer, because this affects the phylacogenic immune defense The following examples explain the practical application.
Die Behandlung von malignen Tumoren (z.B. des Mammakarzinoms mit Knochenmetastasen) erfolgt mit Einzelpräparaten aus maternem Anteil der Plazenta, jugendlichem Thymus, Leber, Milz, Pankreas, Gehirnanteilen, Nabelstrang oder Epiphyse zusammen mit dem Organ des Primärtumors oder dem Sitz der Metastasen, in diesem Falle Brustdrüse und Knochenmark, zusammen mit jugendlichem Testes ohne Spermatogenese wegen der Hormonabhängigkeit des Tumors oder mit Mischungen aus mindestens 2 der eingangs genannten Komponenten zu gleichen Teilen bei immunologisch tolerogener Dosierung der wässrigen Lösungen in Verdünnungen pg, ng, µg und mg aus den voll wasserlöslichen und emulgierbaren Organtrockensubstanzen bzw. -pulvern. Durch langsame i.v.-Injektion oder Tropfinfusion mit üblichen Infusionslösungen,denen die Präparate zugesetzt sind, werden am 1. Tag der Behandlung 4-6ml, am 2. Tag 6 ml der Verdünnung pg, am 3. und 4. Tag je 6 ml der Konzentration ng, am 5. Tag 6 ml der Konzentration pg und am 8. Tag 2ml, am 11., 15. und 19. Tag je 4 ml und danach 2mal wöchentlich (Montag und Donnerstag) je 2 ml der Konzentration mg/ml, ansteigend bis zu einer Gesamtmenge pro Applikation von 1 g-appliziert. Bei stationärer Behandlung kann die Anwendung intensiviert werden. Am 1. Tag 10-20 ml der Konzentration pg verteilt auf 2-3 Gaben, am 2. Tag 10-20 ml der Konzentration ng, verteilt auf 2 Gaben und am 3. Tag 10-20 ml der Konzentration ug, sodann am 4. Tag 2-4 ml, am 7.Tag 4-10 ml, am 9. Tag 10-20 ml der Konzentration mg/ml. Danach dann 2mal wöchentlich (Montag, Donnerstag) je 2-6 ml der Konzentration mg, gegebenenfalls ansteigend auf eine tägliche Gesamtmenge von 1 g. Zusätzlich werden Präparate der gleichen Organzusammensetztung in Konzentration mg/ml in Kapseln oder in Liposomen, Suspensionen, oral 3mal täglich 8-10 Tropfen verabreicht.Malignant tumors (e.g. breast cancer with bone metastases) are treated with single preparations from the maternal part of the placenta, youthful thymus, liver, spleen, pancreas, brain parts, umbilical cord or epiphysis together with the organ of the primary tumor or the location of the metastases, in this case Breast gland and bone marrow, together with juvenile test without spermatogenesis due to the hormone dependence of the tumor or with mixtures of at least 2 of the above-mentioned components in equal parts with immunologically tolerant dosing of the aqueous solutions in dilutions pg, ng, µg and mg from the fully water-soluble and emulsifiable Organ dry substances or powders. By slow iv injection or drip infusion with conventional infusion solutions to which the preparations have been added, 4-6 ml of the dilution pg on day 1 of treatment, 6 ml of concentration on day 2 and 6 ml of concentration on day 3 and day 4 ng, on the 5th day 6 ml of the concentration pg and on the 8th day 2ml, on the 11th, 15th and 19th day 4 ml each and then twice a week (Monday and Thursday) 2 ml each of the concentration mg / ml, increasing up to a total of 1 g applied per application. With inpatient treatment, the application can be intensified. On the 1st day 10-20 ml of the concentration pg divided into 2-3 doses, on the 2nd day 10-20 ml of the concentration ng, divided into 2 doses and on the 3rd day 10-20 ml of the concentration µg, then on the 4th Day 2-4 ml, on the 7th day 4-10 ml, on the 9th day 10-20 ml of the concentration mg / ml. Then twice a week (Monday, Thursday) 2-6 ml of the mg concentration, possibly increasing to a total daily amount of 1 g. In addition, preparations of the same organ composition in mg / ml concentration are administered in capsules or in liposomes, suspensions, orally 8-10 drops 3 times a day.
Die Behandlung kann als Intervallbehandlung bis zum Verschwinden der Symptome oder als 3-Wochen-Kur durchgeführt werden. Eine Wiederholung ist bei erneuter Verschlechterung des Krankheitszustandes jederzeit möglich, sonst aber in sich verlängernden Abständen von 2, 3, 4 und 6 Monaten. Zur Tumorprävention bei Risikopatienten werden Wiederholungskuren in Abständen von 1/2 bis 1 Jahr durchgeführt.The treatment can be carried out as an interval treatment until the symptoms disappear or as a 3-week course. A repetition is possible at any time if the condition worsens again, but otherwise at increasing intervals of 2, 3, 4 and 6 months. For tumor prevention in high-risk patients, repeat cures are carried out at intervals of 1/2 to 1 year.
Vor der ersten i.v.-Applikation empfiehlt es sich auch bei Wiederholungsbehandlungen eine Vortestung der Reaktionslage durch i.c.-/s.c.-Injektionen von 2 ml der Konzentration pg vorzunehmen. Bei ausbleibender Reaktion kann dann 1-4 Stunden danach mit der i.v.-Applikation begonnen werden. Bei der Daueranwendung kann nach der 3-wöchigen Behandlung auf i.m. oder s.c.-Injektionen eventuell mit Retard- oder Depot-Präparaten übergegangen werden. Diese sollen pro Tag Wirkstoffmengen von µg bis g freisetzen.Before the first i.v. application, it is also recommended to carry out a preliminary test of the reaction situation with i.c.- / s.c.-injections of 2 ml of the concentration pg. If there is no reaction, IV application can be started 1-4 hours later. In the case of continuous use, after 3 weeks of treatment, i.m. or SC injections may be used with sustained release or sustained release preparations. These should release amounts of active ingredient from µg to g per day.
Bei Androgen-hormonabhängigen Prostatakarzinom werden neben Prostata-Präparaten,die dem Mutterboden der Metastasen entsprechenden und solche aus Ovar verwendet. In ähnlicher Weise verfährt man auch bei anderen Tumorarten.In the case of androgen-hormone-dependent prostate cancer, prostate preparations that correspond to the topsoil of the metastases and those from the ovary are used. A similar procedure is used for other types of tumors.
Bei Tumoren des Zentralnervensystems wird zunächst eine immunologische Toleranz durch systemische Anwendung, auch gegen Präparate aus Gehirnanteilen induziert und dann ab der 3. Behandlungswoche zusätzlich zu der toleranzerhaltenden Applikation intrathekal in Abständen von 3-4 Tagen jeweils 2-4 ml der Konzentrationen pg, ng ug, eventuell auch mg appliziert. Sonst kann bei anderen Tumorarten nach Erzeugung der Immuntoleranz gegen das Präparat auch intra-tumoral, -pleural, -peritoneal, -artikulär injiziert werden.In tumors of the central nervous system, immunological tolerance is first induced by systemic use, also against preparations from brain parts, and then from the 3rd week of treatment, in addition to the tolerance-preserving application, 2-4 ml of the concentrations pg, ng ug in intervals of 3-4 days , possibly also mg applied. Otherwise, other tumor types can be injected intra-tumoral, -pleural, -peritoneal, -articular after the immune tolerance to the preparation has been established.
Bei bestehender Immuntoleranz können andersartige Faktoren, die indirekt über Antikörperbildung auf das Tumorgeschehen einwirken, z.B. solche,die nach dem Verfahren der EPA 801066.6 gewonnen sind, auch immunogen nach den Gesichtspunkten der immunologischen Immunisierung durch Boosterung angewandt werden. Zur Toleranzerhaltung gegenüber den direkt wirksamen Faktoren müsse-n-diese wie beschrieben fortlaufend weiter verabfolgt werden. Dazu ist auch die Anwendung als Depot- oder Retard-Präparate möglich.If there is an immune tolerance, other factors that have an indirect effect on tumor development via antibody formation, e.g. Those obtained by the method of EPA 801066.6 can also be used immunogenically from the standpoint of immunological immunization by booster. To maintain tolerance to the directly effective factors, these must be administered continuously as described. It can also be used as a depot or sustained release preparation.
In Tierversuchen an Mäusen, Ratten und Hamstern wurde festgestellt, daß die tolerogen dosierten löslichen Organextrakte zu einer signifikanten Verbesserung der therapeutischen Wirkung bezüglich der Regression der Tumormenge, dem Ausbleiben von Metastasen und der Allgemeinwirkung führen.gegenüber der Anwendung von Organpräparaten mit korpuskulären, nicht löslichen Bestandteilen. Nach anfänglicher Tumorregression beginnt dort 4-6 Wochen nach Behandlungsbeginn ein erneutes Tumorwachstum. Dieses wird durch die tolerogene Anwendung von voll löslichen Organextrakten verhindert.In animal experiments on mice, rats and hamsters it was found that the tolerogenously dosed soluble organ extracts lead to a significant improvement in the therapeutic effect with regard to the regression of the tumor amount, the absence of metastases and the general effect compared to the use of organ preparations with corpuscular, non-soluble components . After initial tumor regression, tumor growth begins again 4-6 weeks after the start of treatment. This is prevented by the tolerogenic use of fully soluble organ extracts.
Erzeugung von Toleranz gegen voll wasserlösliche Organextrakte, die unspezifisch eine überschiessende immunologische Reaktionslage mit der Tendenz zur verstärkten Antikörperbildung normalisieren und die bei exogenen Allergien wie auch bei immunopathogenen Autoimmunerkrankungen, bei Verbrennungen, Organtransplantaten und gegen Operationsfulgen angewandt werden, ohne daß eine spezifische Toleranz gegen die pathogenen Antigene oder Allergene erzeugt wird. Es werden dazu voll lösliche Organtrockensubstanzen, bzw. -pulver aus foetalem Thymus, foetaler Milz, foetalem Anteil der Plazenta, Nebenniere und Lymphknoten, einzeln oder in beliebiger Mischung aa verwendet. Diese Präparate können auch gleichzeitig mit der spezifischen Desensibilisierung und Toleranzerzeugung gegen exogene wie endogene pathogene Antigene oder aber mit der sogenannten Gegensensibilisierung unter Verwendung von zum Antigen umgewandelten Antikörpern bzw. Reaginen angewandt werden.Generation of tolerance to fully water-soluble organ extracts, which non-specifically normalize an excessive immunological reaction situation with a tendency to increase antibody formation and which are used in the case of exogenous allergies, as well as in immunopathogenic autoimmune diseases, in burns, organ transplants and in relation to surgical fullergens, without a specific tolerance to the pathogenic Antigens or allergens is generated. Fully soluble organ dry substances or powder from fetal thymus, fetal spleen, fetal part of the placenta, adrenal gland and lymph nodes, individually or in any mixture aa are used for this purpose. These preparations can also be used simultaneously with specific desensitization and tolerance generation against exogenous and endogenous pathogenic antigens or with so-called counter-sensitization using antibodies or reagents converted to the antigen.
Das Behandlungsschema unterscheidet sich vom Beispiel 1 durch die Anwendung von jeweils nur 2-4 ml der verschiedenen Verdünnungsstufen. Die Behandlung wird nach' dem Verschwinden der Symptome 1-2 Wochen weitergeführt. Die Applikation kann auch s.c. oder i.m. erfolgen.The treatment regimen differs from example 1 in that only 2-4 ml of the different dilution levels are used. The treatment is continued for 1-2 weeks after the symptoms have disappeared. The application can also be s.c. or i.m. respectively.
Die Wirkung dieser Therapie konnte am Absinken der Immunglobuline E und dem Ansteigen der Reaktionsschwelle für die Auslösung allergischer Reaktionen festgestellt werden. Es ist wahrscheinlich,daß der Therapieerfolg auch bei allergisch disponierten Patienten dauerhafter ist, als bei der reinen Desensibilisierung und der Verwendung von nicht wasserlöslichen Organpräparaten, bei nicht tolerogener Dosierung.The effect of this therapy was determined by the lowering of the immunoglobulins E and the increase in the reaction threshold for triggering allergic reactions. It is likely that the therapeutic success will be more permanent even in allergy-prone patients than with pure desensitization and the use of non-water-soluble organ preparations, with non-tolerogenic dosing.
Zur Desensibilisierung und Erzeugung von Oberkreuz-Toleranz bei immunopathogenen Autoaggressionskrankheiten wie z.B..der chronischen Nephritis oder den Kollagenosen werden voll lösliche Präparate analog den Organarten verwendet, gegen-die sich die Autoantikörper richten. Die Behandlung erfolgt zunächst s.c. oder i.m. mit ansteigender Dosierung von pg über ng zu µg. Bei starker Symptomatik am 1. Tag evtl. 3 und am 2. Tag 2mal täglich in Abständen von 2-3 Stunden, sodann einmal täglich jeweils 1-4 ml. Bei guter Verträglichkeit wird zur nächst höheren Konzentration übergegangen. Nach Erreichen der µg-Konzentration wird die i.v.-Applikation beginnend mit der höchsten Ausgangsverdünnung von jeweils 2-4 ml der ansteigenden Konzentration bis mg/ml als Injektion oder als Infusionen eingesetzt. Eine gleichzeitig kombinierte Anwendung von Präparaten entsprechend Beispiel 2 beschleunigt den Therapieerfolg. Dieser konnte objektiviert werden durch Absinken der bestehenden Eosinophilie der Lymphozytose und der Autoantikörpef.To desensitize and create upper cross tolerance in immunopathogenic autoaggressive diseases such as chronic nephritis or collagenosis, fully soluble preparations analogous to the types of organ against which the autoantibodies are directed are used. Treatment is initially s.c. or i.m. with increasing dosage from pg to ng to µg. If the symptoms are severe, on the 1st day possibly 3 and on the 2nd day 2 times a day at intervals of 2-3 hours, then once a day in each case 1-4 ml. With good tolerance, the next higher concentration is used. After reaching the µg concentration, the IV application is used as an injection or as an infusion, starting with the highest initial dilution of 2-4 ml of the increasing concentration up to mg / ml. Simultaneously combined use of preparations according to Example 2 accelerates the success of the therapy. This could be objectified by a decrease in the existing eosinophilia of lymphocytosis and the autoantibody.
Zur Erzeugung von Oberkreuz-Toleranz vor einer allogenen Nierentransplantation wird mindestens 5 Tage vor der Transplantation, möglichst aber 2-3 Wochen vorher, mit Präparaten aus foetaler und jugendlicher Schweineniere in ähnlicher Weise wie in Beispiel 1 behandelt. Es können dabei Mischpräparate entsprechend Beispiel 2 zusätzlich mitverwendet werden. Zur Aufrechterhaltung einer stabilen Toleranz werden alle 3-4 Tage bis zu g-Mengen in Konzentrationen mg/mI zunächst i.v. appliziert und später dann Retard-Präparate implantiert, die pro Tag Proteinmengen von µg bis mg freisetzen.To produce upper cross tolerance before an allogeneic kidney transplantation, at least 5 days before the transplantation, but if possible 2-3 weeks beforehand, treatment with preparations from fetal and juvenile pig kidney is carried out in a similar manner as in Example 1. Mixed preparations according to Example 2 can also be used. In order to maintain a stable tolerance, every 3-4 days up to g quantities in concentrations mg / ml initially i.v. Applied and later implanted sustained release preparations that release protein amounts of µg to mg per day.
Tierexperimentell konnte bei der Überpflanzung von Rattenhaut auf Mäuse eine signifikante Verlängerung der Überlebenszeit der Transplantate durch die Vorbehandlung der Mäuse mit wasserlöslichen Extrakten aus Rattenhaut, gegenüber nichtbehandelten Tieren nachgewiesen werden.In animal experiments, a significant increase in the survival time of the grafts could be demonstrated in the transplantation of rat skin to mice by pretreating the mice with water-soluble extracts from rat skin compared to untreated animals.
Zur Erzeugung von Überkreuz-Toleranz bei Organinfarkten und Apoplexien werden Präparate analog der betroffenen Organart möglichst frühzeitig nach dem Infarktereignis bei rascher Konzentrationssteigerung wie in Beispiel 1 appliziert. Gleichzeitig können Mischpräparate entsprechend Beispiel 2 angewandt werden. Die Behandlung wird bis zur klinischen Ausheilung und Normalisierung der Laborparameter fortgesetzt. Bei Apoplexien erfolgt ab dem 3. Tag zusätzlich die intrathekale Anwendung von jeweils 1-2 ml der Verdünnungen pg und ng. Die Behandlung kann zusätzlich zu der üblichen Intensivtherapie durchgeführt werden. Die Konzentrationen und Applikationsmengen dürfen nur bei einwandfreier Verträgl'ichkeit gesteigert werden, sonst muß die Konzentration und die Applikationsmenge mindestens um 1-2 Stufen, d.h. Dezimalen gesenkt werden. Dies gilt für alle Indikationen.To produce cross tolerance in organ infarctions and apoplexies, preparations analogous to the organ type concerned are applied as early as possible after the infarction event with a rapid increase in concentration as in Example 1. At the same time, mixed preparations according to Example 2 can be used. Treatment continues until clinical healing and normalization of laboratory parameters. In the case of apoplexies, intrathecal administration of 1-2 ml of the dilutions pg and ng is also carried out from the 3rd day. The treatment can be carried out in addition to the usual intensive therapy. The concentrations and application quantities may only be increased if they are perfectly tolerable, otherwise the concentration and the application quantity must be increased by at least 1-2 steps, i.e. Decimal can be lowered. This applies to all indications.
Verwendung der löslichen Organpräparate als Antigen zur Testung auf bestehende Antikörperbildung. Es werden die präventiv oder therapeutisch verwendeten Lösungen von ug und mg/ml gegen Blutserum oder Körperflüssigkeiten wie liquor spinalis, Gelenkpunktate, Exsudate im Gel-Diffusionstest untersucht. Die Präparate können auch radioaktiv markiert zum Radioimmunassay (RIA-Test) verwendet werden. Desweiteren sind in vivo Allergenteste, z.B. konjunktival, epidermal und intrakutan möglich.Use of the soluble organ preparations as an antigen for testing for existing antibody formation. The preventive or therapeutically used solutions of µg and mg / ml against blood serum or body fluids such as liquor spinalis, joint punctates, exudates in the gel are Diffusion test examined. The preparations can also be used radioactively labeled for radioimmunoassay (RIA test). Furthermore, allergen tests are possible in vivo, eg conjunctival, epidermal and intracutaneous.
Claims (24)
gekennzeichnet durch die wiederholte Applikation in sich verlängernden Intervallen von Stunden bis zu 5 Tagen von Lösungen bzw. Emulsionen in ansteigender Konzentration von mindestens 2 Verdünnungsstufen, einschließlich mg, bis zu g - Mengen intravasal oder als Zusatz zu Infusionen, sowie in allen bekannten systemischen und lokalen Applikationsformen, auch als Dispersionen in Verbindung mit Lösungs- oder Resorptions-verzögernden Stoffen oder als Bestandteil von Liposomen oder Wasser-in-Öl-Emulsionen:
characterized by repeated application in prolonged intervals from hours to 5 days of solutions or emulsions in increasing concentration of at least 2 dilution levels, including mg, up to g - quantities intravascularly or as an additive to infusions, as well as in all known systemic and local Application forms, also as dispersions in connection with dissolving or absorption - delaying substances or as a component of liposomes or water-in-oil emulsions:
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT82100130T ATE27913T1 (en) | 1982-01-11 | 1982-01-11 | PRODUCTS FOR INTRAVASAL APPLICATION OF WATER-SOLUBLE OR EMULSABLE ANTIGEN ORGAN EXTRACTS. |
| DE8282100130T DE3276616D1 (en) | 1982-01-11 | 1982-01-11 | Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts |
| EP82100130A EP0083673B1 (en) | 1982-01-11 | 1982-01-11 | Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP82100130A EP0083673B1 (en) | 1982-01-11 | 1982-01-11 | Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0083673A1 true EP0083673A1 (en) | 1983-07-20 |
| EP0083673B1 EP0083673B1 (en) | 1987-06-24 |
Family
ID=8188812
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP82100130A Expired EP0083673B1 (en) | 1982-01-11 | 1982-01-11 | Products for intravasal application of water-soluble or emulsifiable antigenic organ extracts |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0083673B1 (en) |
| AT (1) | ATE27913T1 (en) |
| DE (1) | DE3276616D1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3835472A1 (en) * | 1988-10-18 | 1990-04-19 | Tetzner Volkmar | Product for cellular therapy and process for the manufacture of this product |
| EP0673652A1 (en) * | 1992-07-21 | 1995-09-27 | NIKOLAENKO; Alexandr, Nikolaevich | Biologically active agent having immunomodulating properties, method for its obtaining and pharmaceutical preparation based on it |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1033374B (en) * | 1955-11-02 | 1958-07-03 | Dr Med Karl Theurer | Process for the production of preparations from isolated placenta parts |
| FR1957M (en) * | 1962-01-19 | 1963-08-05 | Rolland Lab A | Organ extracts. |
| FR2138509A1 (en) * | 1971-05-27 | 1973-01-05 | Pivert Michel Le | Compsns contg placental tissue and procaine - for treatment of cancer |
| DE2338970A1 (en) * | 1973-08-01 | 1975-02-27 | Boettger Kg Pharmazeutische Un | Standardised, stabilised, water-soluble placenta extracts - used in the treatment of wounds and swellings e.g. ulcers |
-
1982
- 1982-01-11 EP EP82100130A patent/EP0083673B1/en not_active Expired
- 1982-01-11 AT AT82100130T patent/ATE27913T1/en not_active IP Right Cessation
- 1982-01-11 DE DE8282100130T patent/DE3276616D1/en not_active Expired
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1033374B (en) * | 1955-11-02 | 1958-07-03 | Dr Med Karl Theurer | Process for the production of preparations from isolated placenta parts |
| FR1957M (en) * | 1962-01-19 | 1963-08-05 | Rolland Lab A | Organ extracts. |
| FR2138509A1 (en) * | 1971-05-27 | 1973-01-05 | Pivert Michel Le | Compsns contg placental tissue and procaine - for treatment of cancer |
| DE2338970A1 (en) * | 1973-08-01 | 1975-02-27 | Boettger Kg Pharmazeutische Un | Standardised, stabilised, water-soluble placenta extracts - used in the treatment of wounds and swellings e.g. ulcers |
Non-Patent Citations (3)
| Title |
|---|
| CHEMICAL ABSTRACTS, Band 76, Nr. 21, 22 März 1972, Zusammenfassung 125294z, Seite 364, Columbus, Ohio, (US) V.H. MORALES et al.: "Immunosuppressive action in vitro by a bovine spleen extract" & Z. Naturforsch. B 1971, 26(12) 1339-40 * |
| CHEMICAL ABSTRACTS, Band 79, Nr. 7, 20 August 1973, Zusammenfassung 38638h, Seite 29, Columbus, Ohio, (US) E. GARCIA-GIRALT: "Immunosuppressive effect of an inhibitor of DNA synthesis obtained from bovine spleen" & Advan. Antimicrob. Antineoplastic Chemother., Proc. Int. Congr. Chemother., 7th 1971 (Pub. 1972) 2, 177-9 * |
| IVAN ROITT "Essential immunology" 4. Auflage, 1980, Blackwell Scientific Publications Oxford, (GB) Seiten 105-110; 129-130; 198-201 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3835472A1 (en) * | 1988-10-18 | 1990-04-19 | Tetzner Volkmar | Product for cellular therapy and process for the manufacture of this product |
| EP0673652A1 (en) * | 1992-07-21 | 1995-09-27 | NIKOLAENKO; Alexandr, Nikolaevich | Biologically active agent having immunomodulating properties, method for its obtaining and pharmaceutical preparation based on it |
| EP0673652A4 (en) * | 1992-07-21 | 1996-07-03 | Nikolaenko Alexandr N | Biologically active agent having immunomodulating properties, method for its obtaining and pharmaceutical preparation based on it. |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0083673B1 (en) | 1987-06-24 |
| DE3276616D1 (en) | 1987-07-30 |
| ATE27913T1 (en) | 1987-07-15 |
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